Targeting apoptosis is one of the major strategies for cancer therapy. Essentially, most of the conventional cancer therapeutic drugs that are in the clinical use induce apoptosis and in part necrosis of malignant cel...Targeting apoptosis is one of the major strategies for cancer therapy. Essentially, most of the conventional cancer therapeutic drugs that are in the clinical use induce apoptosis and in part necrosis of malignant cells and therefore prevent cancer progression and metastasis. Although these cytotoxic anticancer drugs are important weapons for killing cancers, their toxic side effects limited their application. The molecularly targeted therapeutics that are based on the deeper understanding of the defects in the apoptotic signaling in cancers are emerging and have shown promising anticancer activity in selectively killing cancers but not normal cells. The examples of molecular targets that are under exploration for cancer therapy include the cell surface receptors such as TNFR family death receptors, the intrinsic Bcl-2 family members and some other intracellular molecules like p53, MDM2, IAP, and Smac. The advance in the high-throughput bio-technologies has greatly accelerated the progress of cancer drug discovery.展开更多
The BH3 mimetics targeting the interaction between the BH3-only proteins and their prosurvival Bcl-2family proteins have shown enormous potential as cancer therapeutics. Herein, seven analogues targeting anti-apoptoti...The BH3 mimetics targeting the interaction between the BH3-only proteins and their prosurvival Bcl-2family proteins have shown enormous potential as cancer therapeutics. Herein, seven analogues targeting anti-apoptotic Bcl-2 proteins derived from the Bim BH3 domain via sequence simplification and/or modification are described. The in vitro binding affinity on anti-apoptotic Bcl-2 proteins and cell killing activity were evaluated. The results showed that analogues could significantly bind to target proteins and exhibited anti-cancer effect against three cancer cell lines. Of particular interest were the analogue SM-5（KD= 9.48 nmol/L for Bcl-2） and SM-6（KD= 0.08 nmol/L for Bcl-xL）, which exhibited improved binding affinity compared with the lead Bim（KD= 16.90 nmol/L for Bcl-2 and 22.2 nmol/L for Bcl-xL, respectively）. These results indicated that the peptide sequence containing the four hydrophobic side chains occupying pockets within the BH3-recognition cleft of anti-apoptotic Bcl-2 proteins might be the minimum sequence required for the bioactivity and the active core region of Bim. Promising inhibitors of anti-apoptotic Bcl-2 proteins with high bioactivity might be designed based on the active core.展开更多
基金Supported by A grant from National Key Sci-Tech Special Project of Ministry of Science and Technology of ChinaNo.2008ZX10002-020+1 种基金the National Natural Science Foundation of ChinaNos.30973390 and 81272249(S.W)
文摘Targeting apoptosis is one of the major strategies for cancer therapy. Essentially, most of the conventional cancer therapeutic drugs that are in the clinical use induce apoptosis and in part necrosis of malignant cells and therefore prevent cancer progression and metastasis. Although these cytotoxic anticancer drugs are important weapons for killing cancers, their toxic side effects limited their application. The molecularly targeted therapeutics that are based on the deeper understanding of the defects in the apoptotic signaling in cancers are emerging and have shown promising anticancer activity in selectively killing cancers but not normal cells. The examples of molecular targets that are under exploration for cancer therapy include the cell surface receptors such as TNFR family death receptors, the intrinsic Bcl-2 family members and some other intracellular molecules like p53, MDM2, IAP, and Smac. The advance in the high-throughput bio-technologies has greatly accelerated the progress of cancer drug discovery.
基金financially supported by Postdoctoral Applied Research Project of Qingdao(No.861605040085,to CZ,SW)Grant of Innovation Plan in Biomedical Research of Qingdao City(No.15-10-3-15-(28)-zch,to SW)
文摘The BH3 mimetics targeting the interaction between the BH3-only proteins and their prosurvival Bcl-2family proteins have shown enormous potential as cancer therapeutics. Herein, seven analogues targeting anti-apoptotic Bcl-2 proteins derived from the Bim BH3 domain via sequence simplification and/or modification are described. The in vitro binding affinity on anti-apoptotic Bcl-2 proteins and cell killing activity were evaluated. The results showed that analogues could significantly bind to target proteins and exhibited anti-cancer effect against three cancer cell lines. Of particular interest were the analogue SM-5（KD= 9.48 nmol/L for Bcl-2） and SM-6（KD= 0.08 nmol/L for Bcl-xL）, which exhibited improved binding affinity compared with the lead Bim（KD= 16.90 nmol/L for Bcl-2 and 22.2 nmol/L for Bcl-xL, respectively）. These results indicated that the peptide sequence containing the four hydrophobic side chains occupying pockets within the BH3-recognition cleft of anti-apoptotic Bcl-2 proteins might be the minimum sequence required for the bioactivity and the active core region of Bim. Promising inhibitors of anti-apoptotic Bcl-2 proteins with high bioactivity might be designed based on the active core.
